No decrease in fracture risk despite 15 years of treatment evolution for multiple myeloma patients:A Danish nationwide case-control study

RATIONALE: While treatment strategies for multiple myeloma have evolved radically over the last decades, little is known about the risk of fractures for symptomatic multiple myeloma patients over time. OBJECTIVE: To determine the effect of different treatment periods (1996-2000, 2001-2006 and 2007-2011) on the risk of fractures in patients with multiple myeloma. METHODS: This retrospective case-control study included patients with multiple myeloma in Denmark, using the Danish National Health Service. Cases were defined as patients who had sustained a fracture between 1996 and 2011, and controls were those without a fracture. Exposure was defined as an ICD code for multiple myeloma. Vertebral fractures, gender, and age were considered in secondary analyses. Conditional logistic regression was used to estimate odd ratios (ORs) of fracture risk, and the analyses were adjusted for comorbidities and recent drug use. RESULTS: The study population consisted of 925,341 cases, and the same number of matched controls, of whom 1334 patients with multiple myeloma. Among cases, the risk of any fracture was higher in multiple myeloma patients compared to patients without multiple myeloma (any fracture: ORadj[95% CI] 1996-2000: 1.7[1.3-2.3]; 2001-2006: 1.3[1.1-1.6]; 2007-2011: 1.7[1.4-2.2]). Although fractures were mainly non-vertebral, the risk of vertebral fractures in particular was higher in multiple myeloma patients (vertebral fracture: ORadj[95% CI] 1996-2000: 3.5[1.4-8.6]; 2001-2006: 4.0[1.9-8.2]; 2007-2011: 3.0[1.6-5.7]). CONCLUSIONS: Despite new treatment strategies and improved supportive care, this study showed no decreased fracture risk for multiple myeloma patients over time. New treatment strategies, even if they have a positive impact on overall survival, offer no guarantee for a corresponding reduction in bone lesions

High prevalence of peripheral neuropathy in multiple myeloma patients and the impact of vitamin D levels, a cross-sectional study

Purpose: Peripheral neuropathy (PN) is common in patients with multiple myeloma (MM). We hypothesized that the relationship between hypovitaminosis D and PN described in diabetes mellitus patients may also be present in MM patients. Methods: To study this potential association, we assessed the incidence of hypovitaminosis D (vitamin D < 75 nmol/L [= 30 ng/mL]) in smouldering and active MM patients in two Dutch hospitals. Furthermore, a validated questionnaire was used to distinguish different PN grades. Results: Of the 120 patients included between January 2017 and August 2018, 84% had an inadequate vitamin D level (median vitamin D level 49.5 nmol/L [IQR 34–65 nmol/L]; mean age: 68 years [SD ± 7.7]; males: 58%). PN was reported by 69% of patients (n = 83); however, of these 83 patients, PN was not documented in the medical records of 52%. An association was found between lower vitamin D levels and higher incidence of PN in the total population (P = 0.035), and in the active MM patients (P = 0.016). Conclusion: This multi-centre cohort study showed that PN and hypovitaminosis D are common in MM patients, and addressing low vitamin D levels in the treatment of MM patients might be beneficial in reducing the risk of PN. More attention for PN is warranted, as PN is underreported by clinicians. Further research is needed to fully understand the implications of vitamin D in the development of PN in patients with MM. Clinical trial registration: Netherland Trial Register NL5835, date of registration July 28, 2016

Dual neutralisation of interleukin-17A and interleukin-17F with bimekizumab in patients with active ankylosing spondylitis: results from a 48-week phase IIb, randomised, double-blind, placebo-controlled, dose-ranging study

Objectives Bimekizumab selectively neutralises both interleukin (IL)-17A and IL-17F. We report efficacy and safety in a phase IIb dose-ranging study in patients with active ankylosing spondylitis (AS).Methods Adults with AS (fulfilling modified New York criteria) were randomised 1:1:1:1:1 to bimekizumab 16 mg, 64 mg, 160 mg, 320 mg or placebo every 4 weeks for 12 weeks (double-blind period). At week 12, patients receiving bimekizumab 16 mg, 64 mg or placebo were re-randomised 1:1 to bimekizumab 160 mg or 320 mg every 4 weeks to week 48; other patients continued on their initial dose (dose-blind period). The primary end point was Assessment of SpondyloArthritis international Society (ASAS) 40 response at week 12 (non-responder imputation (NRI) for missing data).Results 303 patients were randomised: bimekizumab 16 mg (n=61), 64 mg (n=61), 160 mg (n=60), 320 mg (n=61) or placebo (n=60). At week 12, significantly more bimekizumab-treated patients achieved ASAS40 vs placebo (NRI: 29.5%-46.7% vs 13.3%; p<0.05 all comparisons; OR vs placebo 2.6-5.5 (95% CI 1.0 to 12.9)). A significant dose-response was observed (p<0.001). The primary end point was supported by all secondary efficacy outcomes. At week 48, 58.6% and 62.3% of patients receiving bimekizumab 160 and 320 mg throughout the study achieved ASAS40, respectively (NRI); similar ASAS40 response rates were observed in re-randomised patients. During the double-blind period, treatment-emergent adverse events occurred in 26/60 (43.3%) patients receiving placebo and 92/243 (37.9%) receiving bimekizumab.Conclusions Bimekizumab provided rapid and sustained improvements in key outcome measures in patients with active AS, with no unexpected safety findings versus previous studies.Pathophysiology and treatment of rheumatic disease

Stress en luchtwegtoxiciteit: een literatuuroverzicht en een vooruitzicht op (de) experimentele analyse

In de huidige risicoevaluatie spelen de gevolgen van cumulatieve blootstelling aan diverse milieucontaminanten voor de volksgezondheid een steeds grotere rol. Immers, mensen worden veelal blootgesteld aan een mengsel van contaminanten zoals chemicalien, geluid, stank of straling. Het is momenteel onduidelijk hoe en in welke mate effecten van verschillende milieucontaminanten interfereren. Het huidige onderzoeksproject is gericht op de interactie tussen stress en luchtwegtoxiciteit. Stress kan worden geinduceerd door diverse verstoringen, zowel intrinsiek als extrinsiek. Derhalve wordt stress gedefinieerd als "het totaal aan biologische reacties op een verstoring in het milieu van het organisme welke als negatief wordt ervaren. Geluid is een veel voorkomende verstorende factor, die leidt tot gevoelens van onbehagen en eventueel tot een chronische stress conditie. Het wordt steeds duidelijker dat een toestand van onbehagen of chronische stress nadelige gevolgen kan hebben voor de algehele gezondheid. Het immuun systeem in het bijzonder blijkt gevoelig te zijn voor de negatieve effecten van stress, hetgeen kan leiden tot een verhoogde gevoeligheid voor ziekten. Luchtvervuiling is een van de meest onderkende vormen van milieuvervuiling gezien de enorme verspreiding in het milieu, de grote aantallen mensen die er mee in aanraking komen alsmede de gezondheidseffecten die erdoor worden veroorzaakt. Primair worden vooral de ademhalingswegen (de neus, de bronchiale pijpen en de alveoli) aangetast door luchtweg toxicanten. Ozon wordt beschouwd als een van de meest toxische agentia en wordt gevormd door fotochemische reacties in de lucht, vooral tijdens perioden van zomer-smog. De toxische effecten van ozon omvatten oxydatie reacties met lipiden, eiwitten en DNA in het longepitheel, een vermindering van de longfunctie, een verhoogde permeabiliteit van het longepitheel, oedeem-vorming, ontstekingsreacties en hyperreactiviteit. Op diverse niveaus kunnen de effecten van stress (veroorzaakt door chronische geluidshinder) interfereren met de toxische effecten van ozon. Bijvoorbeeld op het organismaal fysiologisch niveau (veranderde ventilatie, metabolisme), biochemisch niveau (gevoeligheid voor oxydatie reacties, cellulaire antioxidant status) of op het immuunsysteem (bijv. ontstekingsreacties). Echter, op dit moment is het niet bekend of dergelijke interacties ook werkelijk optreden. Derhalve zou de interactie tussen stress en luchtwegtoxiciteit experimenteel onderzocht kunnen worden. Een dergelijk experimenteel onderzoek zou uit te voeren zijn in drie opeenvolgende fasen: de ontwikkeling van een dier-experimenteel chronisch stress-model op basis van geluidshinder, het aantonen van interferentie op bepaalde niveaus bij cumulatieve blootstelling en het aantonen van daadwerkelijke interactie tussen de twee stressoren. Dit laatste zou uitgevoerd kunnen worden met diverse geluidsintensiteiten en diverse ozon concentraties. Op basis van een dergelijk onderzoek zou het mogelijk zijn een evaluatie te maken van de mogelijke interactie tussen geluidshinder enerzijds en ozon blootstelling anderzijds. Dit zou dan leiden tot een beter inzicht in de mogelijke effecten van cumulatieve milieubelasting en de gevolgen hiervan voor de volksgezondheid.In present risk assessment, the effects of cumulative exposure to disturbing forces and pollutants in the environment are of increasing concern. People are exposed to a mixture of contaminants like chemicals, noise, bad smell or radiation. However, at present it is unclear how and to what degree different environmental factors and contaminants interfere. The present research project focuses on the interaction between stress and airway toxicity. Stress may be induced by numerous intrinsic and extrinsic disturbing forces. In this respect, stress is defined as the total set of biological responses to a disturbance in the organism's environment which is appraised as negative. Noise is a widespread environmental contaminant causing a feeling of annoyance and eventually a chronic stress condition. During the last decades, it is becoming clear that a state of annoyance or chronic stress may have detrimental effects on general health. The immmune system in particular appears to be sensitive to stress which may result in an increased susceptibility to disease. Air pollution is one of the most acknowledged contaminants due to its universal spread, the high number of people exposed, and the adverse effects observed. The respiratory tract, including the nose, bronchia and alveoli, is the primary target site for air pollutants. Ozone is considered as one of the most toxic components of photochemical air pollution, especially during summer smog episodes. The toxic effects of ozone (as observed in both experimental animal and human studies) consist of oxidative reactions with membrane lipids, proteins and DNA within the lung epithelium, transient decrements of respiratory function, increased epithelial permeability, edema, inflammation, and hyperreactivity. At several levels, stress effects (induced by chronic noise exposure) may interact with ozone toxicity. These interactions may be found at the general physiological level (e.g. altered ventilation, metabolic rate), the biochemical level (e.g. susceptibility to oxidation reactions, antioxidant defense capacities) or within the immune system (e.g. inflammatory effects, altered host defence capability). However, these interactions are presently hypothetical and need to be verified by experimental analysis. Such an experimental study should be performed in three consecutive steps: the development of a chronic stress-model based on noise-exposure, the demonstration of cumulative effects between noise-stress and ozone toxicity, and finally the demonstration of interaction between the two contaminants using several noise intensities and several ozone concentrations. Using this experimental approach, an evaluation on the interaction between noise exposure and ozone toxicity can be performed. This will result in an increased understanding of the risk for human health during exposure to multiple environmental contaminants.DGM/L

Voltage-gated and Ca(2+)-activated K+ channels in intact human T lymphocytes. Noninvasive measurements of membrane currents, membrane potential, and intracellular calcium.

Voltage-gated n-type K(V) and Ca(2+)-activated K+ [K(Ca)] channels were studied in cell-attached patches of activated human T lymphocytes. The single-channel conductance of the K(V) channel near the resting membrane potential (Vm) was 10 pS with low K+ solution in the pipette, and 33 pS with high K+ solution in the pipette. With high K+ pipette solution, the channel showed inward rectification at positive potentials. K(V) channels in cell-attached patches of T lymphocytes inactivated more slowly than K(V) channels in the whole-cell configuration. In intact cells, steady state inactivation at the resting membrane potential was incomplete, and the threshold for activation was close to Vm. This indicates that the K(V) channel is active in the physiological Vm range. An accurate, quantitative measure for Vm was obtained from the reversal potential of the K(V) current evoked by ramp stimulation in cell-attached patches, with high K+ solution in the pipette. This method yielded an average resting Vm for activated human T lymphocytes of -59 mV. Fluctuations in Vm were detected from changes in the reversal potential. Ionomycin activates K(Ca) channels and hyperpolarizes Vm to the Nernst potential for K+. Elevating intracellular Ca2+ concentration ([Ca2+]i) by ionomycin opened a 33-50-pS channel, identified kinetically as the CTX-sensitive IK-type K(Ca) channel. The Ca2+ sensitivity of the K(Ca) channel in intact cells was determined by measuring [Ca2+]i and the activity of single K(Ca) channels simultaneously. The threshold for activation was between 100 and 200 nM; half-maximal activation occurred at 450 nM. At concentrations &gt; 1 microM, channel activity decreased. Stimulation of the T-cell receptor/CD3 complex using the mitogenic lectin, PHA, increased [Ca2+]i, and increased channel activity and current amplitude resulting from membrane hyperpolarization